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I had been turned on by the fact my doc spent most of the interview looking at me, hum..., carefully, intensely. I had expressed concerns that my cheeks had sunken a bit. I was a bit defiant.He said that , being an MSM community doc, he never hesitates to prescribe treatment, that they actually perform in his same clinic and that first justified request will grant me immediate access, no questions asked. Yet, he insisted, that I have to come to realize that aging (and a bit of anxiety) will change my face, eventually. He was adamant that this is not Lipo and that he will keep it under surveillance.Why did he had to add that my skin and other anatomical features are actually well preserved for our (same) age ? and with that charming smile of his, then ...

I have recently realized that I had made 2 big MISTAKES in MY understanding of the MI risk associated with ABACAVIR.

These 2 easy to make mistakes should be demystified.

Turning 50 soon, I was really unhappy to hear about that DADS outcome, given my obsession on that subject (family history...)Quite naturally, I had second thoughts and somehow wished I had been offered Truvada (which may be a nice drug otherwise, I do not know, so please, do not drag me into a discussion on Truvada itself, this is not the point, here)

Here, I will mention a medication I do not take (Truvada, the most common current alternative to Kivexa), something I usually refrain from, but this is where MY mistake lies.

MY FIRST MISTAKE*****************

My (false) understanding was to consider that the original DADS shows that ABC demonstrates an ADDITIONAL risk compared to OTHER NRTIs (which in MY mind included Tenofovir and FTC, the components of Truvada, the most currently used combined NRTI) and therefore to think (falsely) that DADS demonstrates an additional MI risk between KIVEXA and TRUVADA.

The truth is the original report for DADS DO NOT demonstrates an additional cardiologic risk of KIVEXA vs TRUVADA. I though it did, after (wrongfully, my bad...) understanding second hand reports, review and comments or posts on this forum. But the fact is that the original paper DOES NOT demonstrates an additional cardiologic risk of KIVEXA vs TRUVADA. (the 3TC component of Kivexa is usually considered as being so similar to the FTC component of Truvada, so that the differentiator is ABC vs TNF).

Because this is what the original (first) DADS report says about Tenofovir:

quote: Patients participating in D:A:D have also received other drugs as part of their nucleoside/nucleotide backbone, including emtricitabine and tenofovir. There is currently insufficient follow-up time (<2 years on average) among patients receiving these drugs to assess reliable associations with the rate of myocardial infarction.(unquote)

In other words Tenofovir is not part of the 'OTHERS NRTIs' category. It is simply not covered by the FIRST DADS original report.

Nonetheless, it is included in further reports (as DADS is an on going follow up study)

But, here, the authors are very cautious... Because ABC was introduced on the market MUCH before (5 years?) TNF, the data collected do not span over the same period and less data is collected on TNF

As of 2011, there are, to my knowledge 3 longitudinal studies including cardialogic risk evaluation, including ABC, AND VERY LARGE, multi ethnic cohorts. (IMHO, the smaller danish cohort, does not qualify in that definition).They are DADS, ANRS and VA cohort.

Here below is the comparison table, with conclusions relative to ABC vs TNF (who cares about other NRTIs in 2011...)

This was MY first mistake: to think that DADS was CLEARLY demoting ABC vs TNF.

A side note: same caution if you are considering modern PIs that were NOT included in early DADS reports

Duration of inclusion (hence statistical relevance) can not be ignored.

MY SECOND MISTAKE*****************

was to consider that ABC is multiplying MY MI risk by the (usually referred to) risk ratio of 1.9 (later downgraded to 1.7) (which is almost as high as smoking) (note: the multiplicative risk ratio for smoking is 2 to 3 depending on studies).

Here again this is NOT true. DADS itself points out that the additional risk is VERY HIGHLY stratified per baseline (i.e. pre-meds) cardiovascular risk.

The risk (if any) is ONLY for those with a higher baseline cardiovascular risk (scored, I suppose, on the pretreatment Framingham score-sheet).

The evidence provided by DADS original report itself is EXTREMLY GRAPHIC:

Thank you Eric for all your information from the viewpoint of a patient starting Viramune and Kivexa (Epzicom). I found it VERY interesting, especially as Im currently on Nevirapine and the very 'outdated' Combivir. Ive been looking at replacing the Combivir with something else and the choices so far are between Truvada or Epzicom.Your letters have been informative and great to read, Thanks!!!Steve

Thanks for the comments. Appreciated. (BTW, my PM box receives this kind of nice comments on a regular basis: thanks you all!)

The good news for you is that, since you have tolerated your current combo for long, you can always switch back to V&C, should you find V&T or V&K not of your liking. The switch would simplify your schedule to once daily, which I find convenient, because except for business trips, I do not have to bother about carrying pills. I just keep some spares in car/backpack. The alarm by the bed does the trick for me. I do not even have a wristwatch

I recently found some statistics (which I'll post soon) that support the general understanding about that combo: discontinuation rate is a bit higher than others at initiation, but continuation rate after year 2 seems extremely stable

I knew the test results would be good (but I did not know yet it would bring an additional bonus):UD (hey, what would you expect?)CD4: 739CD8: 738CD4%: 31,2CD4/CD8 ratio : 1.0HDL: 0.70 ; LDL: 1.45, everything else well within range...No single health issue during this long and rainy winter (except a bit of tiredness, fatigue, lack of energy...)

yielded a 3% 5 year mortality risk (the lowest value that this calculator can provide, given my age , which I can not change, is 2% i.e. if VAcs index = 0)(I get a slightly higher score (6) due to a lower level of platelets, eventhough, they have increased recently)

Had a bit of discussion with Doc about a few people who had kindly PM'd me and expressed fears about NVPHe said that Doc who are careful in patient selection before choosing Viramune are equally happy than with EFV, that he prescribes EFV more often that NVP, but has had more adverse events with EFV than NVP.

Discussed that I am feeling a bit alone on this less usual combo.He said that NVP had been banned from some hospital because of patient death, but that was before the screening rules were implemented.That it also depends on doctors education, experience and confidence, (and availability...) which leads to a situation where NVP is never used in some parts of the countryHe said that, on the other hand, there are others regions where V&K is 'hype' and the trendiest thing in town . Patients show up and demand this comboMay be some people are reading this thread after all...

Discussed the new cardiologist who will now be in charge of my 'yearly' check up. Brillant HIV/cardio specialist (wrote books, publications, etc.) and extremely cute, assistant doctor, who is right on my type!(I wonder if this will show on the cardio test when he performs it...)Sex drive is back somehow, which he commented was a good therapy... Well... In our offer and demand local gay scene there is little room for courting and romance... So, I am not always very comfortable with my doc 'recommendation' that I should have more (extramarital) activities. I fell like a dinosaur in this sex consumption scene. I prefer to have an open discussion with doc, rather than be offended by comments that are, IMHO, out of the main scope of a doc visit. Nonetheless, my position of a listed (ex-) gay activist who happened to have found happiness with the (most unexpected) person he loves most ( and happens to be of the opposite gender) is a very sensitive subject. A bit more tact in this matter would be nice, but I think this is way out of his mind set.

The good news*************When he gave me the prescription he underlined one new thing:The prescription is valid for 6 months !!He said that one benefit of V&K is that once people are stable on it, they are very stable and with this kind of numbers, there is no point in seeing me as often as before.And that unless something shows up the 'yearly full hospital check up' is from now on once every 2 years!

Boy!.. after all the stress of this fancy combo initiation, here comes the rewardI was not even looking forward to less doc visits (*) and blood work, but, this, indeed will lower the burden by ca. 50%

I have regained a confidence in myself that I though was gone for ever...I feel suddenly much better!

(*) I like my Doc, but with regards to his color matching taste, there is room for improvement

Doctors have hundreds of patients. To expect them to remember the co-habitation situation of all of them is naive. I'll take brains over social banter any day and be happy with the results of less pills, increased efficacy and stabilization beyond expectations. As a patient, if I were to notice how "cute" my cardiologist was and "just my type", I would be the last to criticize my physician's bedside manner.http://forums.poz.com/Smileys/default/shocked.gif I'd gladly settle for doctor's visits of 2-3 times a year vs. the 6 I endure, especially if I was told I could "date" again. Your physician didn't say to go out and have unsafe sex, he said to have more sex. Now that you are feeling better, I hope you do just that with any consensual and educated person you choose.http://forums.poz.com/Smileys/default/wink.gif The choice is yours, not his.http://forums.poz.com/Smileys/default/kiss.gif

Thanks for posting. While this thread is focused on treatment, (especially when on a less common, once demoted, combo) and not about doc and patient relationship, I do not mind commenting on doc patient relationship as it is a significant part of treatment/healing. (and otherwise would be a boring medical thread)

I am more than happy with the choices he has made with/for me thus far. He a fabulous doctor. he's got lot's of good connections.I have also expressed my interest in participating in clinical trials (and we are doing prescreening tests), but, I'll live the final say up to him.Doc and I have concording/converging views on a number of issues and discordant on some other.The 'special' relationship is not on a personal level. It is on a risk management which goes beyond routine clinical care. And I do not mind giving some insights:

Just to give some background, in our local socialized health care, HIV is ONLY handled through hospital. There is no such thing as private practice. This may sound 19th century to a lot of people, especially in the US. Nonetheless, my doc was authorized, on an experimental basis, to open the first ever (and so far only) private practice in our country (based on his long hospital experience and contribution as a board member of local guidelines). This experimental private pratice is actually partly subsidized (by the state) and he still works at he hospital.

I feel privileged (and gratefull) for the extra care and time he gave me. That my doc is a more-than-usual important person to me may have transpired through this thread. It is a given fact. My choice. While I have received some PMs asking if I am attracted/in love with doc: the answer is simply NOAm I a more-than-usual patient to him ? I hope not, I am sure he treats other patients with the attention they deserve according too their specifics (treatment failure, (illegal) migrant status, complication of any sort, etc). But there is a bit more to it:A- I know for a fact that I am (one of) the very first patient in his all new private practice, and most certainly the first newly diagnosed to be sent to him directly rather than hospital first (as is standard practice here). His other first patients were old timers on follow up. (originally this experimental private practice was started to take some burden off the state hospital and restricted to follow up of 'stable' patients). He did show obvious surprise when I showed up as a newly -diagnosed and his office was still humid with the all new paint and furniture still wrapped in plastic!B- I am (by far) not the first patient he initiates on Viramune. I am not the first patient he initiate on Kivexa. But the first he initiate on both (his hospital boss forbids that...)

Treatment is a journey. A special one for me (obviously) and also for him (not medically speaking, but as the sole, unsupervised, decision maker, in an entrepreneurial sense)

The (visible) success of his experimental private clinic and of (so far so good) success of my own treatment makes me a special-patient no more.

In a sense, the fact that I am put on the lightest possible maintenance schedule makes me happy, but, sure, I'll lose that special care and doc availability that this 'unusual' combo initiation requires.

Commenting on sex / doc / love (and doc taste in clothes) is normally not part of this thread and I will refrain from now on.

Through this forum and other reading I realize how lucky I am (in a sense): less than 25 % of US Hivers are UDs, and about 50% where I live...

I have just lost a special status (my initial doc visits were twice a month!) and gained a new one ('stable' patient) and I hope the readers will excuse a bit of venting and whining

I also hope that prospective users of this 'fancy' combo will still like reading this one single, no-more-unique patient experience

CROI: HIV+ People with CD4 Counts Above 500 Match Life Expectancy of General Population

and other life expectancy articles are among most popular story on aidsmeds as well. Earlier reports had looked at people with CD4 > 500 AND VL < 50.

Needless to say, for people like myself who could be treated early and have, thus far, been good responders, this is good news.

The stats are one thing and the patient perspective, another.

This less than usual combo (Viramune / epzicom) is not for every one: treatment naives with higher CD4s are excluded, and, since the risk of failure at initiation is higher, may be not for people with low nadir (at least a a first line combo), as they do not have the luxury of time. etc...

Yet one question is rarely addressed: how many of people under long term HAART, in a setting of good availability of care and meds are UD and have CD4 > 500.

addresses mostly economical aspects. Yet, it provides 3 very interesting tables:- Patient distribution based on CD4-cell count and viremiaand mortality...- Patient distribution based on CD4-cell count andviremia-Efficacy data: immunologic response per different treatment regimen (side note: V&K is not listed, but very close combos such as V&T and S&K are listed: initial success rates is lower but extremely stable over the years.)

When care is available, 'normal' life expectancy (the >500 strata) is for 25% of patients and 'near-normal' life expectancy (the 350< CD4 < 500 strata) is for another 25% of patients. That still makes ca. 50% !

half full or half empty glass depending how you look at it, this is still a very good number considering the nasty nature of the virus...

My doc seems happy with the optimal response to my treatment.Feeling a bit lonely on V&K, it just makes me feel a bit better about it to learn, that, (where meds are accessible) good response is far from rare.

The above article is about the virologic, immunologic and clinical outcome restricted to NON-AIDS defining patients ONLY. All patient with and AIDS defining condition are excluded. Only EFV or NVP initiating patients are considered.

Same as DADS, this is a prospective study... Good as a whistle blower, but prone to analysis bias and interpretation. See:

In this post; let's focus on one of the first conclusion: virologic failure is higher, in this asymptomatic virtual cohort, with NVP than with EFV and let's put things in the patient perspective...

Virologic failure rate is higher in the NVP group. (BTW, it is also in cohorts including all patients). This results is far from unexpected. NVP is often said to have a lower barrier to resistance.

This terminology may be a bit improper.

Browsing through available literature I think there are 2 schools:

Concept 1

NVP is resistant to mutations that are less likely to be identified in an initial resistance test. An initial resistance test can only pick up mutations that present at above 20 % level. If NVP is resistant to a mutation that hovers at 10%, it is not picked up at initiation by the first resistance test. It is sometimes pointed out that a single dose of NVP can built resistance. then that resistance goes in hiding, behind fitter quasispecies. Upon initiation, what was below 10% now becomes 20 % and so on...(*)

Concept 2

The virus can mutate a lot... The high mutation rate is due to inherent infidelity of HIV reverse transcriptase (RT) and RNA polymerase II and may be partly caused by cellular cytidine deaminases such as hA3G (APOBEC3) (which the virus jams thanks to its Vif factor). If a drug allows for more mutants, and replication keeps going, ultimately, by chance, one mutant will be fit enough and resistant, hence the virologic failure. (**). Bad news for those who experience that...The good news for those NOT experiencing virologic failure though, is that those mutants, that might partly refill the reservoir, are most likely defective. This could be extremly Beneficial for people successfull under NVP

Therefore:If NVP initiation protocol would call for a resistance test prior to initiation AND a resistance test within the first few weeks (when VL is still > 500 or 1000 depending on labs)(as I did myself), potential Virologic failure would be identified earlier and the virologic outcome would be better.

Therefore it is NOT NVP, per se, which is the problem, it is the way NVP is initiated and resistance monitored...(if resistance tests were more sensitive or cheaper, then virologic failure would be less likely).Here the problem is not the drug itself but the initiation protocol or practice.

Is the take home lesson for someone who initiates therapy in 2012 same as for those who did way back in 2000 in this cohort? Of course not...

NVP carries more risk of VF. Fine. We knew that already. I was really scared myself and this is the reason why I started this thread (BTW)

Back in the years 2000 this was a definitive lowdown for NVP (vs EFV), because in case of failure your options were limited. But in 2012, early pick up of VF warrants an early switch to Etravirine (same class) or RAL (INSTI class) or even Maraviroc (if applicable and available)

So the risk is (slightly) higher, but you've got your arse covered.

You are jumping with smaller size parachute, but with a big time safety net (RAL/ PIs/ MVC/Etr) that initiators back in 2000 did not have... Yet, so many times I see posts where people are told: take this pill once a day for 2 weeks then twice daily from day 15 and we will see you in 3 months (sometimes 6...) unless you have a rash.

As a patient you want to be damm sure the airbags are available and will trigger on time !

Sorry for the long post. Next post, about immunologic outcome, will be shorter...

Stay tuned

Cheers Eric

PS: for further reading

(*)there are many academic reference for this. Let's just quote:

quote:Our study also reveals that the excess treatment failure observed in the NVP arm is strongly associated with detection of NVP-resistant mutants missed by standard population genotype. (unquote)

I am not sure if you can assist here? Are you able to shed some insight re one of the biggest drawbacks to treatment with NRTIs and that is the decrease in mitochondrial DNA which has with prolonged use has been linked to tissue toxicity including premature aging, body shape changes, peripheral neuropathy (PN) and myopathy.

I am aware that Abacavir is not considered as toxic as previously used NRTIs. Well that is the current thinking now.

Management of potential mitochondrial toxicity during long term nucleoside analogue therapy would therefore remain a challenge for many of us.

How would one know of any potential underlying cell damage taking place on NRTI treatment before symptoms would present? If we decided to continue on NRTI treatment, how could we manage the potential toxicity? Would being pro active in including nutritional supplements help lessen the risk of toxicity in any way?

I tried bringing this to my attention of my specialist but he was not able to shed any real light on this topic. I thought that perhaps during your extensive research you may have stumbled across some relevant information.

One of the above cited article provides in depth explanation about how NRTIs work:

I quote

Importantly, unlike NRTIs, NNRTIs do not require intracellular metabolism to exert their activity...(unquote)

NRTIs do not have a direct activity, they need some kind of enzymatic transformation and it is the resulting products that have the inhibitory effect (not the NRTI themselves): hence the mandatory intracellular metabolism

First, I never (almost) comment on drugs I do not take. Therefore, I cannot state anything on NRTI sparing regimen. Most of them are PI based, and PIs also come with their share of management issues. And depending on the initial resistance test not everyone has the luxury of choice, anyway.

The point that I hope to come to in the next few post, is one key understanding: NRTIs act BEFORE integration of replicate DNA bits in host chromosome, right after viral entry, whereas PIs act at the other end of the cycle, before the exit.

In layman's words, NRTIs and NNRTIs are trying to prevent the bank robbers (who have successfully passed the entrance door to access the vault room, whereas PIs prevent the bad guys to leave the vault/bank

I think you should put your (legitimate) concerns about these long term toxicities into perspective:Well treated people (like yourself) may lose a few months to a year of life expectancy to HIV + HAART, admittedly. Blue color workers lose 5 years to white collar, and smokers something between 5 and 10 years.

As far as I am concerned, it may well take me 3 years to get adjusted to the meds, but I can see things improving one tiny step after the other. I hardly ever notice it now on facial change or fatigue, etc.

I will have a post dedicated to liver health management, though, as I have found a few things that I still need to confirm and may be usefull to my pill buddies

I am working on some exciting new findings that may inspire hope to people with a treatment profile like yours

If, indeed, this is a manageable condition, then it needs to be understood and managed...

Historically, VL decay was thought to be a single phase logarithmic decay(for those unfamiliar with logarithmic decay, think of radioactive elements such as iode which has a short half life). It was early understood that the decay was at least bi-phasic (a sharp initial decay, followed by a slower one). At the end of this biphasic decay, the virus should have disappeared and treatment could be ended and the infection made history. Unfortunately not the case ...

Dr Siliciano then introduced the concept of a tri-phasic decay (a model later refined to quadri phasic) in which the last phase has such a long half life (44 months) (think of plutonium) that people would have to remain on treatment for more than an estimated 66 years

- it is free- the fit between model and clinical data is really convincing- it offers a CD4 dynamics that is at the same time simple and convincing enough- it is consistent with the disappointing results of treatment intensification- it is compatible with Dr Siliciano's model of a slowly decreasing (non replenishing) reservoir- it is compatible with the alternative vision that the reservoir replenishes (cell-free transmission as well asA. Sigal 's Cell-to-cell spread (transplication) http://www.nature.com/nature/journal/v477/n7362/full/nature10347.html

unfortunately:- it is difficult to understand- it applies mostly to the context of successfull treatment and good immunologic response

Finally, it offers an alternative vision to the logarithmic decay paradigm, on which very early works were based. A paradigm that has recently lead to set backs in reservoir suppression trials (as it assumes that the reactivated latent CD4 will have a logarithmic decay by intrinsic self death, which they don't, and do not have the second chance of a logarithmic decay due to an adverse environment, since the milieu has lost its anti-HIV activity, as demonstrated by Pr. Siliciano himself).

The steady state equations are not very different from Pr. Siliciano's system of three ordinary differential equations published in page 3 of:Low-level HIV-1 replication and the dynamics of the resting CD4+ T cell reservoir for HIV-1 in the setting of HAARThttp://www.biomedcentral.com/1471-2334/8/2/

Steady state equations are just easier to understand...

Here is my humble understanding of the equations as these equations are the key to a-cure-within-one's-lifetime; the set (1) of 3 equations is in page 2

They consider the steady state of healthy CD4S (subtly named 'targets'), steady state of infected CD4s and steady state of VL.

(note: residual free RNA, a measurement surrogate for VL, due to dying CD4s are not accounted for since this applies to post-second decay, here, they imply VL = active virus, which is not exactly the VL reported on one's lab sheet)

the second:infected CD4s are made of recently infected CD4s, plus reservoir (latent) minus dying (infected) CD4sthe number recently infected CD4s, itself, is the number of CD4s multiplied by VL (in other words exposure the active virus) and attenuated by a factor combining drug efficacy and virus infectivity

(of note: it exposes the Dr Siliciano paradigm that drug efficacy, in a successfull combo, is 100% efficient, which regardless of virus infectivity makes that multiplier equal to zero and and therefore equate the number of infected CD4s to the latent, quiescent reservoir only)

Here, the interesting points are :- reservoir replenishment is zero if infectivity is zero (i.e. CR and/or X4 receptors are successfully blocked)- a less efficient drug that would hinder more the infectivity (fitness) of the virus could very well lead to less reservoir replenishment (on the next cycle) than a more efficient drug that would otherwise not change the virus fitness (+)

The third:

Uninfected CD4s are equal to their proliferation (++) (birth, duplication, etc.) minus their death rate and minus those which have been infected

Okay... This is a long and technical post, and not necessarily bullet proof.Yet this is the necessary base for next post which is about the Nevirapine (Viramune) immulo-virologic apparent PARADOX

Nevirapine, a fairly 'old', somewhat marginalized (usage ca 16%), drug, receives pretty bad reviews and any article showing its relative inferiority (usually vs EFV) receives wide publicity (including on this site). On the other hand there is a growing evidence that NVP has also some very interesting advantages, but those reports get unnoticed.I have answered about 15 PMs from people so anxious about NVP, who finally did fine...

Let's expose the Nevirapine Paradox and cheer them up!

For the sake of easier understanding, try to visualize a chart or cursor where we scale virologic and immunologic outcome. Some sort of a 'progress bar'

To the left we place virologic failure along with immunologic non-response: bad news. Here, in that area of the chart, well..., EFV bests NVP. The Odds ratio (risk multiplicator) is ca. 1.5 (most likely less now that closer monitoring and screening is enforced, IMHO)

Somewhat towards the right, we place satisfactory immunologic response (CD4 > 350, for example) and VL < 50 : clinically encouraging news.In that area, differences are almost inexistant and the pros and cons are more in the range of secondary aspects (cholesterol, CNS effects, ease of use, cost...)

Further to the right, we can place the best that we can measure. It is not necesserally clinically relevant, but there is most likely a status better than just CD4 > 350 / VL < 50

And even much further to the right are 'cures' obtained by medication, which would be the Graal of Pharma-cure; (bio-cure is out of the scope of this efficiency chart). (Thus far considered never-reached, this unchartered area is open to research and speculation)

Since CD >= 500 and VL < 50 seems to confer a minimal additionnal death risk, there is no evidence that Full-responders will fare better than good responders, but, on our chart they are one step closer to the Graal.

Here is as cohort review of 'full responders':http://www.ncbi.nlm.nih.gov/pubmed/22915460Nevirapine use, prolonged antiretroviral therapy and high CD4 nadir values are strongly correlated with undetectable HIV-DNA and -RNA levels and CD4 cell gain.

The 420 patient cohort is restricted to patients who are VL <50 within 6 months and remain stable. The above report looks at 'Full responders'. They represent only 6% of patients who maintain UD (patients who are UD , vl <50 is ca. 50% of treated patients in that region). So, full responders represents ca. 3% of patients under HAART .Current combo is recorded to see if some drugs are more favorable. Obviously, in that socialized health care cohort, the newest, most recently approved drugs are not present. Therefore, the statement below does not include these.

With the sole and only exception of Viramune, no 'classical' drug was associated to 'full-reponse'.

Obviously starting treatment earlier and at higher CD4 Nadir makes it more possible to qualify to this group. After all, if your Nadir is 600, it is unlikely that you are to miss one of the 3 criterias (CD4 > 500)...

That NVP is the only drug associated to full-response is already an intriguing observation.

More interesting is the odds ratio: 3 ! this is very high

If you would want to 'rate' NVP vs EFV at the left end of our chart, NVP is 1.5 'lesser' than EFV. but on the other side of the chart NVP bests any other (incl. EFV) by a factor 3

This is what I call the Viramune paradox...

- it is a lesser drug if your fail- it is a better drug if you succeed.

Why this happens ? is this of importance for moving further to the right (Pharma-cure) ?

Stay tuned and I hope NVP users will enjoy the further developments such as: Is it possible to monitor progress towards full response ? ...

It did not make the headlines, but, what follows may matter to nevirapine users.

The 'discovery' or 'smoking gun' proof of cell-to-cell transmission by Alex Sigal is a turning point. It made the headlines.

It has lead A. Sigal to write an interesting (although not bullet proof) 'perspective' in Nature

Underlying this publication is a generation as well as a conceptual quarrel between moderns and ancients, between reasoning by infectivity persistence (Sigal) and reasoning by number persistence (Siliciano)

When I read A. Sigal's 'perspective' article (unfortunately, not free..), I had a feeling it would be hurting the numerists feelings and some strong academic response would follow.

Right on: Pr. Siliciano's just published his 'own' 'perspective'... It is strongly worded and tries to establish dominance of his concepts (it is R. Siliciano's numerist concepts that lead to believe that it would take 66 years, hence life long, to eradicate the virus under current, modern HAART). To make his point Robert Siliciano not only used his remarkable crystal clear style, he also made available for free...

Why this is of importance here? because 'numerist' perspective fails to explain the Viramune Paradox, where as a competition between numerical persistence and infectivity persistence may explain it...

Stay tuned, this is going to be a REALLY interesting academic debate that may change the perceptions that we have about competing drugs long term efficiencies and the (somber) perspective of a never ending treatment.

Eric

PS: (*) added on 09/29:(R. Siliciano writes: (quote)An interesting recent paper suggests that in the vicinity of a virus-producing cell, the exposure of adjacent cells to multiple infection events reduces the efficacy of antiretroviral drugs on a probabilisticbasis (Sigal et al., 2011). However, cells with multiple proviruses are rare in vivo (Josefsson et al., 2011) (/unquote)

In fact this last point, apparently silencing Sigal, is not as strong as it seems because Josefsson's measurements where made in blood and Josefsson's conclusion is (quote) our results indicate that most CD4+ T cells in the peripheral blood contain only one copy of HIV-1 DNA (/unquote). He did not write in vivo... he wrote in PBMC... and CD4 in blood are ca 2% of all CD4s... And Sigal already acknowledges that cell-to-cell transmission can (almost) not happen in CIRCULATING liquid (such as blood)...

So... Why is 'full response' of interest (A) and is there a status even better than 'full responder' (B) ?

A - As per R. Siliciano's above mentioned article: (quote) Eradication efforts will likely be attempted only in patients on HAART who have had sustained suppression of viral replication for years, and therefore the cells responsible for the second phase (+) may not represent a barrier to eradication(/quote)(+) he refers, here, to residual replication

In other words, any one interrupting treatment at a point on the treatment progression timeline where residual, under the radar, replication has not ceased is bound for... a viral rebound (no pun intended)

Therefore 'full responders' are among the best candidates for the upcoming eradication trials. So anyone willing to participate in an eradication trial should at least be a full responder (or similar). Not convinced? Then browse for eradication clinical trials and look at the inclusion criterias.

And the best way to actively maximize chances to be a full responder:- long duration of treatment (not under patient's control, recently treated will have to be patient)- earlier entry into treatment (not so much under patient's control)- use of Viramune. (a viable option for some patients, but not all...)(or modern drugs? we do not know yet, since treatment duration is a main key factor)

My point here is certainly NOT to say that NVP is superior to other meds ... I am not interested in dog fights about drugs. I just want to convey to the 'poor' patient who is not eligible for the newest, fancier caviar regimen, and is being scared of this slightly riskier drug, that, on the long run things may turn out much more favorable than expected

But there is more...

B - on our progress bar, where the 'Pharma-cure' is at the rightmost end, is there any reachable status that is even better than full responder ? Yes there is... The happy few (may not a few as we might think...) are labelled 'secondary controllers'. Ever heard of Secondary controllers ? Most likely not...

These are patients who, generally disregarding medical advise, have interrupted treatment and have had no need (mostly) to resume treatment.Elite controllers are 'natural controllers'; 'secondary controllers' are patients who were not natural controllers, but who, after years of successful treatment have been rewarded by this 'secondary control' status.

So, we have this all new video game, where you can raise up from hell, to reasonable health condition, and then move forward to a 'full responder' status then further to that exciting 'secondary control' status, which, from a patient perspective is just wonderfully great. (to date, 5 years off-treatment with clinically good enough control for some patients...)

'Secondary controllers' are a new urban legend ? Is there a clinical trial to back this up ?Well... I certainly did not make this up !Skeptical? Then do you own research or just stay tuned for more on that super status and, more interestingly, how it relates to your current or prospective NVP combo and provides more fuel to that interesting Viramune paradox ...

Stay tuned for more

Eric

PS Abacavir users will love the irony of this finding in here:http://www.ncbi.nlm.nih.gov/pubmed/22994586Cardiovascular risk factors and carotid intima-media thickness are associated with lower cognitive performance in HIV-infected patients:... abacavir use was independently associated with a better cognitive performance ... (no kidding)

The work is based on a small, but well monitored, socialized health care cohort of the Institute of Tropical Medicine of Antwerp, including over 1700 patients. This is more a case report than a clinical trial and one could think it is only anecdotal.

Let's grant those doctors in Antwerpen (Belgium) with an ounce of credibility. HIV is their daily turf. There may be some methodological mistakes in the report, but once again, this is from experienced HIV specialists who are not new to this field.

Once striking number is that about 10% of patients (eligible for free treatment) drop out despite medical advise... It blows my mind, I could not believe it. The younger generation has been 'told' about but has never 'seen' AIDS in action, but still...

Among the drop outs 2.5% have been labelled 'secondary controllers' (4 divided by 160)

Obviously anyone just entering treatment has very little chance to control the virus, thus, it would be inappropriate to think that 2.5% of a given cohort are potentially secondary controllers. On the other hand, it is reasonable to think that among the good eggs who did not drop therapy despite many many years of successful treatment, there are some secondary controllers in the closet. Therefore it is not unreasonable to think that in this particular cohort, ca. 5% are secondary controllers.

Is there something special about Antwerpen ? Why other studies have not picked up those SC ?Are these fakes ? (people telling their doc they are not taking meds while importing generics on the side ?)(in socialized healthcare where meds are FREE, why would one want to do that ?)Are there people out there not telling their docs that they have stopped taking the meds (but with good control, the doc can not find out ?)

Well... That is for those doctors to find out...

This is not a denialist thread (by any means), it is about NVP (and ABC/3TC). What does this have to do with NVP ?Is this topic going completely out of control ? Without access to patients' treatment history, how can we relate to NVP ? Well... why don't we just try to do that... Hack into the Antwerpen cohort SC's medical history and see the intriguing relationship with Nevirapine (Viramune) ?

Well... We do not really have to hack into people's clinical records... 4 patients have been described and reported as secondary controller.While my current personal target is full control (as described above), this SC status is very attractive and, IMHO, the closest you can get to a Pharma-cure.Fortunately, a detailled case report of 2 of the 4 patients can be found here:Control of viral replication after cessation of HAARThttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3046910/

Those 4 SC (see above post) are very interesting. They divide into 2 subsets:Secondary viral control and good immunologic standing (SC+/I+) : 2 patientsSC and less favorable immunologic standing (SC+/I-) : 2 patients

The 2 patients for whom we have treatment information are (SC+/I+) : 1 patient and (SC+/I-) : 1 patient. 3 of the 4 had been on treatment more than 10 years.

Unless I have missed something, here is what adds our final touch to the NVP PARADOX exposed earlier: the 2 patients for whom treatment is known were on ... Viramune!The studied population is very small and this could be only anecdotal, but, as of today, unless I have missed some other studies, the following seem right to claim:

100 % of fully described secondary controller were on nevirapine !...**************************************************

Considering the usage of NVP is of about 16%, in other words one in six patients, the odds of picking randomly 2 patients in a cohort and find that they are both under NVP is like throwing 2 dice, and get ... a double 61 in 36, less than 3 percent. Is this just by chance ?It can be argued that the numbers are too small to draw a conclusion, yes... but this is intriguing enough.

Still anxious about starting or switching to NVP ? Well, I can understand, but, it is also possibly, one of the best way to get as close as possible to a functional cure

In the next posts, we will see why this might be, and how we can monitor our own treatment progression towards full response and, why not ... SC...

If you would want to learn more about the little molecule that could, I recommend this video

Very scarce information has been published to date with the combination of ABC/3TC/NVPThis is why I keep readers of this thread posted about news findings.

For people looking for ressources about this combo, there is actually very little. Which may help explain why this is thread is, as of today, the most read in this section of the forums.

Finally, a scientific poster has been published on this combo...************************************************************http://www.jiasociety.org/index.php/jias/article/view/18343Effectiveness and tolerability of abacavir-lamivudine-nevirapine (ABC/3TC/NVP) in a multicenter cohort of HIV-infected ARV-experienced patients

prospective users may want to review it.

Understanding the Viramune Video********************************Last post I linked to a video available on the official Viramune Website.Actually, in an other post, I had given a simplistic and quite graphic explanation of how NVP worksI am posting here this same description as a supplement to the above mentioned video.I hope it may help understanding that video, somehow

Variability is due to the infidelity of the reverse transcription process.

The NNRTIS (such as Viramune aka NVP, or Efavirenz aka EFV ) block the reverse transcriptase in a geometrical fashion. (also called steric)

To try to explain in layman's word is kind of difficult.

But think like this.

Visualize a hand holding a baseball, then remove the (large) ball.You hand now has a shape similar to the reverse transcriptase. keep that shape firm

NVP is a small molecule that will geometrically fit between your thumb and first finger, like a small table tennis ball. When the virus DNA approaches the transcriptase, the small ball gets its way. But in some cases it can manage it way through, but not without damage (mutation)

EFV is a larger molecule (like a tennis ball), it fits between the thumb and second finger, thus better blocking transcription process.

More novel NNRTIs are even bigger and fit between thumb and third or even fourth finger, making a complete blockade. In this respect they are more 'efficient'

only one mutation during a faulty reverse transcription can make the virus resistant to NVP. EFV requires two mutations. In that respect as well EFV may appear more efficient.

Nonetheless, mutations have a cost on the virus, which becomes less fit for the next round of infection. Single round efficiency of EFV is superior to that of NVP. but the infectivity of a virus that may have passed the drug (which is not 100% efficient) is less in case of NVP than in case of EFV

The re-contamination rate is combination of infectivity and efficacytherefore this combination is similar with NVP than with EFV AS LONG AS the number of rounds and potential events for mutation is not too high (in the case of NVP). IF VL is high or CD4 is high the odds that an unwanted mutation appears increases.

Which is why there is a limitation on NVP initiation on both VL level and CD4 level.The reason why the cut off value is higher in men than in women is a bit obscure.

It may be related to the fact that proliferation (number of newly created CD4s, hence new 'targets') is higher in women than in men, who, in average have a 100 to 150 higher CD4 count (as observed in the non-HIV infected general population)

The above explanation may have flaws and not scientifically rock solid, but, I hope it helps you...

up-coming posts***************

In the next posts I'll discuss 2 topics that I have been working on recently:

1- a novel method to evaluate in-vivo drug efficiency. This is some work that I am currently documenting and circulating through research community in order to get it further validated. We hope to publish in a scientific publication. Here, I will only give a layman's approach and outlook of what it implies from the patient perspective

2- a tool to allow users evaluate if they qualify for 'full responder' status, even when they have no access to high resolution VL nor reservoir measurements, as these are out of reach in standard clinical follow up.

I hope this will be of interest to those who found some interest in the Viramune paradox.

The little drug that may be a curse for some and a blessing for others as it may help them get to that secondary controller status, which, from a user perspective, might be just as good as a cure.

Last meeting with Doc*********************mix feelings. The cardiologist report had not reached his desk, the CCR5 tropism results had not been provided and we suspect an hospital 'miss'.That was not a good start. We lost a lot of time looking for these missing reports Yet, now that I have been put on crestor (rosuvastatin) 5 mg and responding well to it, my lipid profile is a winner:HDL (the good one) 80 (mg/l)LDL (the bad one) 90

With such good numbers (CD4 , VL, %, ...), he was quite happy!Me not. I wanted to discuss a few things, which he was not prepared to hear, and so we ran out of time.So, I have to redo the CCR5 and go again next month.

good to hear that joining the small numbers of elite controllers are secondary controllers.

what about the issue of inflammation in both of these groups?

inflammation is the silent killer that wears down our body as the immune system is continually being on a high state of alert to control the virus.

meds helps us dampen this immune system hyperactivity.

so one might be lucky to be an elite controller/secondary controller and not need meds but if that means that their body is continually in hyperactive mode to control the virus, not sure if that is a good thing for our bodies due to the negative complications to our bodies arising from inflammation?

Thanks for the question. Happens that I have an appointment soon with a cardiovascular specialist, and, since taking ABC, the question will be on the table.So I hope to get more for you soon...Back in the old (sad) days, that inflammation question was really invisible, well behind a crucial survival crisis. Even weight gain (a concern for some of us) was way out of scope (in an intriguing article published recently an MD said: where is all the wasting gone ? my HIV patients are getting obese ! (LOL) )

You have several issues and they are difficut to sort and rank:- the virus- the virus induced inflammation (or inflamaging)- are the meds enhancing or reducing this inflammation- drug (meds) toxicity

My gut feeling is that the Virus is the key and prime problem including in those inflammaging issues.Clearing the virus is our new target. Maybe we will not be able to eliminate the virus entirely, but we can find hints or better ways to reduce the number of infected cells.

This is a concept very little discussed in the scientific litterature.

From an escape from certain death pespective, if you are starting at CD4 = 10 drug efficiency is more or less defined by the abilty of the drug to increase that number (definition #1). and if that number can slowly go up to 350 who care if X % are monoinfected or moderately infected as long as they can survive and fulfil their role. So from a disease non-progression perspective it does not really matter.

But, an other efficiency definition for drug efficiency (definition # 2) would be the ability to enrich the pool of non-infected cells and reduce the pool of mono or low infected cells.That definition of efficiency is irrelevant when your strategy is to increase the CD4 cell count at what ever costBut now that people are initiating treatment sometimes at CD4 600 or even more, that other definition of drug efficacy (the ability to 'cleanse' the infected cell pool)starts making sense for some patients

I'll document this in a future post.

The '90s or '2000 paradigm was to find an escape route (from certain death)The '2010s for many people this is still the sameBUT, seen from the 'younger' generation patient, initiating with better meds, at a higher CD4 count (a small fraction, but say even if this is only 1-2 % of patients) it is legitimate to live with the expectation that they are engaging a route towards a cure. And all the argumentation about a phamaceutical cure being impossible can be revisited

I think this is the key to the apparent Nevirapine paradox:- as par definition #1, other drugs have proven superior- as per definition #2, a less documented concept, NVP might faring much better

just switched to Viramune 400 mg XR. pill is a little (ca 15%) bigger than one 200 mg immediate release, yellowish vs white. The change was easy enough, but, somehow makes me feel the Kivexa (which I have always suspected to give me anxiety) is a little harder to get by with.Well ... I am on anti-depressants and anti-anxiety for treating depression as well. so it is hard to say.

This results in 2 distinct regimes (either steady state or dynamic) as well as, in some patients a combination of both.This article is not free and not easy to understand...Fortunately, the supporting data, the table of 34 patients (all with VL <50) is in a freely available supplement. Here again not easy to read unless you type the data into a spreadsheet and plot the data with X axis being CD4/C8 ratio and Y axis being the estimated size of infected cells (in part per million, of CD4)(because they have been introduced only recently, very modern drugs such as RAL are not found in patient's regimens)http://www.nature.com/nm/journal/v15/n8/extref/nm.1972-S1.pdftable is in page 6

The relationship between CD4/C8 ratio and infected poll becomes clearly visible. and 4 rectangles (areas) can be identified on the diagramm.

Remarkably, there are not a single of the 34 patients in area D, in other word, in this limited, but well studied group, no-one with a ratio > 1 has a pool of infected cells (in blood) > 200 ppm

On the other hand, whenever the ratio is less than 1 relatively nothing can be said, the infected pool can be just anything from 10 ppm upwards to thousands.

This table provides an interesting snapshot, and, while generalization is questionable, it offer an interesting perspective on dynamics. CD4/CD8 ratio is equal to CD4% divided by CD8 %, and is relatively stable and steady, in the same fashion that CD4 % is. It is moving, but not jumping around especially in those patients where CD4 is on the higher end.

in which he reckons(quote:)Previous small studies have reported that HIV-1 proviral DNA levels are inversely correlated with CD4/CD8 ratio or CD4 T cell counts in successfully ART-treated or naïve HIV-1-infected subjects. Our results confirm and further extend these studies showing a negative correlation between the frequency ofCD4 T cells carrying HIV-1 proviral DNA and CD4/CD8 ratio or CD4 T cells, in infected individuals receiving ART and in whom plasma viremia had been suppressed below the limit of detection for prolonged periods of time. (end of quote)

you will recognize the same L shaped scatter plot with the same A, B, C, D areas as on my diagram above (the only difference is that the vertical boundary is, here, at CD4/CD8 = 1.2, whereas in Chomont's data plot the boundary is at CD4/CD8 = 1.0)

In figure 2 (especially the diagram named 'combined') shows that HIV-specific cytotoxic CD8+ T lymphocytes are much lower when CD4+:CD8+ ratios is over 1.2.

Therefore, while the CD4/CD8 is not a absolute surrogate for a low reservoir (one can have a low reservoir and a lower ratio), anyone with a 'higher' ratio is very likely to have a low reservoir and therefore a good candidate for eradication trials.

In next post we will see the triple play CD4/CD8 ratio, CMV and cancer risk

Hi,Very rarely at at the clinic, would I meet someone looking sick. Yet, last visit was on the day the psychologist was in. The waiting room was filled with people who obviously live with the burden of past medical events or treatments...

To these people, the content of this thread may seem unrealistic and I apologize for that.

Doc visit: nothing special to expect as all numbers are in range (even LDL is low: 0.86). Doc reads the Lab report, he seems concentrated and unconcerned at the same time.

Doc : Whoa... CD4/CD8 = 1.9 (looking happily surprised)Me : (smiling) right on my expectations Doc : ??Me : (smiling as if this was my moment of victory)Doc : Don't worry it will go down (you! spoiler!)Me: Of cause, it might, but not as far as below 1.0Doc: Well... anyway ...This is not about entering a Guinness book contest

Doc once told me, that, as far as it comes to numbers, he sees just about anything you might think of. So as far as it is within range... Yet, he is usually very careful about predicting something (like your CD4 will go up this much, etc.). The only exception is at month 6, when VL became (finally) < 50, he ventured " and in 6 months your ratio will be over 1.0" . Which it almost did...

Me: do you know the difference between kinetics and dynamics (in general)?Doc : No.Me: Kinetics is when you describe things moving (up and/or down), dynamics is when you can describe AND explain by underlying forcesDoc : ??

In fact pharmacokinectics are dedicated to the determination of the fate of substances administered externally to a living organism, where as pharmacodynamics is the study of a drug's pharmacological effect on the body.

There has been a few attempts to model CD4 and CD8 dynamics, but most models have failed when confronted with patients data. The main reason is that, with almost any simple model, one assumes that some parameters remain constant for a period of time. CD4 expansion (proliferation, increase in number by cell division) is increased when a MCH class II must be controlled, and so will CD8 proliferation. These 2 expansions occur in parallel, but their decay follow their own laws (which are different). MCH class II 'attacks' may occurs at a rate/frequency higher than the follow up blood draws.

Then we went on to the physical exam. He was so close to me... While taking my BP, my arm was resting on something soft and comforting that we usually refer to 'hard'He was wonderful, I was so pathetic, we were wonderful

Yet we need mathematical model of CD4 dynamics...It is needed to explain why a Pharma-cure is not impossible and why it has not been (and could not) fully demonstrated yet.

Our models (pending publication) now has a nickname:Single Compression Quadratic Decay of Infected CD4s and Recovery of Uninfected CD4s (in short the SCQD model)

I will spare the reader the resolution of quadratic differential equations and, for the mathematically obsessed, in the interim, you can read this in detail, if you feel frustrated (good luck with it...)

One of the lowdown of our model is that a prerequisite is that NO MCH-Class-II infection should interfere during the period of data collection. Should this happen, and it will happen, then we have to wait for the next favorable period of low immunologic activity.

This is due to the fact that any MCH-Class-II infection will trigger an unmeasurable expansion of CD4s, therefore skewing the decay of the infected cells pool by replenishing it to an unknown level.

Typical infection to trigger a immunologic response involving CD4s are: Influenza, CMV shedding, and, in other words and in the order of appearance in the screen, sorry..., clinical development of late stage AIDS..., all the AIDS-defining opportunistic infections.

Only immunocompetent patient's data can be used and ideally in a non-flu period and hopefully no CMV reactivation period.

While these are very limiting criteria of inclusion for patient's data, I have enjoyed at least 3 extended period of time where those conditions where met (being CMV neg. did help, the flu or flu vaccine, did not...) and therefore 3 calculated points of uninfected CD4 cell pool could be obtained. (please kindly bear in mind that the patient also have to get blood draws at a higher frequency than that covered by health insurance, at his own expense...)

Hit this disease hard and early to get below 1 viral load on meds and keep your CD4/CD8 ratio high so can keep the infected viral reservoirs low......to have your body in a better place (low reservoirs) to take advantage of a cure when it arrives.

Congratulations Eric on those fantastic numbers. I may not post often, but I do keep up with this thread !

I have some labs coming up on August 9th. The last set of numbers took about a 200 point drop in CD4, and some discussion came up, as to a possible switch in regimens. I am still on the 2 separate doses a day of Viramune, and one Epzicom. Was started on an additional dose of 10mg of Lisinopril. This was in addition to the 25mg dose of Hydrochlorothiazide, for blood pressure.

But, I am not going to rush anything, we"ll see how those results come up after the 9th.

There is not a day where I do not think of you... Here, we are working hard here to find reservoir reducing molecules that help people move to full recovery... I will publish what I am allowed to, here, but this is not always easy (for legal reasons)

We hope to establish a new biotec company soon to finance a clinical trial. It is a lot of stress, trying to find a solution to this hurdle, but, the people I am working with are very enthusiastic. It is inspiring.

Still, I do remember your words every time I am rushing to something: one step at a time. Unless resistance occurs, I would never change my current regimen for anything else.

Like you I am on statin. The statin you are using (if my memory is correct) is not much used here any longer since there are some studies that have proven rovustatin to be superior to others.

I can assure you, we are leaving no stone unturned to try to find new keys.

There is not a day where I do not think of you... Here, we are working hard here to find reservoir reducing molecules that help people move to full recovery... I will publish what I am allowed to, here, but this is not always easy (for legal reasons)

We hope to establish a new biotec company soon to finance a clinical trial. It is a lot of stress, trying to find a solution to this hurdle, but, the people I am working with are very enthusiastic. It is inspiring.

you can't understand dynamics in continuous media if you don't understand differential equations!

Blood is a continuous media (a liquid moved by a pump) and all experimental work that has been done and have thus far concluded that HAART is a lifetime treatment (Faucy in 99, Siliciano 2003, SMART study 2006) all share the same underlying hypothesis. That the infected CD4 pool decreases logarithmically, in the same way that VL decreases. In the same fashion that radioelements have a logarithmic decay (measured by the so called half life), we speak of CD4 half lives.

The concept of logarithmic decay (or half live) relies on the predicate that the probability for a radioactive element atom to lose its 'radioactivity' in the course of time is a constant, independent from time. In otherwords a radioelement decay event is a no-memory phenomena.

If the piece of radioactive material you are studying shows persistence, then, it is because some of its elements have a long, long half life (or low probability to die, if you prefer)

This would be very true if the only means of viral persistence was through virions entry alone. Yet there are many type of viral material persistence:

A- some CD4 are new borns (in the thymus or bonemarrow) and a few stems cells (mother cells) may be infected (pretty much like vertically infected babies)B- some viral material will be transferred by virions entryC- some viral material will be transferred by cell-to-cell bridge (A. Segal 2012)D- under homeostatic stabilization, or infection attack, HIV infected CD4s (as well as uninfected CD4s) clone themselves thousands or millions of times, hence refuelling the tank.

A - is memory phenomena (as long as the stems cells maintain memory)B - is a no-memory event, governed by the number of virionsC - is a no-memory, governed by the number of infected CD4 (and the physical proximityD - is a memory effect: a past event (proliferation) drives the persistence dynamics: our SCQD model takes this into account

as promised our model results go graphic

Blue dots are uninfected CD4s (as per our SCQD model)Red ones are short lived CD4s that compensate the shortage in uninfected cell(they are not important at this point and very theoretical concept need for model, hence, I called them 'virtual')

Our model's purpose is to find when the Infected CD4 population goes extinct. Extinction of that species is not exactly eradication. Eradication is when we are sure there is none left and meds can be interrupted. Extinction is more to find when the virus is so low that there is no way it can, by its sole actions, be of any harm. Extinction comes before eradication. As per Pr Siliciano, non-eradication is due to latency of time-isolated, spore-like, quasi-immortal infected CD4 cell. This cannot be modeled by CD4 dynamics. But the almost-zero point of extinction can.

Model validation****************Be be satisfying the model should be self consistent (not show obvious errors), satisfactory confronted to actual lab test results, give the extinction point and we should then find a way to prove that the extinction point is achieved. Finally, it should be predictive.

Self consistent:****************Using Excel, we plot our points and add a default logarithmic trend line.For both sets, the R2 is very close to 1.0 (0.997 and 0.93, respectively).on the drawing below I also show a singular point labelled A.

This shows that there is a lag time before uninfected cell starts to appear. They start to appear ca. 1 month after meds initiation, which is very satisfactory and quite convincing. If the trend had hit the Y axis, that would have meant that there was a population on uninfected cells and, with my initial VL of 50K, I do not think this could be possible. If the virus free cells had started to appear quite many months after meds initiation, this would have been inconsistent with my clinical history

Most population growth, such as bacteria in a Petri dish, do exhibit a tiny lag time. So the existence of the tiny lag time is a good point.

An other point of interest is point G (as in Graal, or Goal) this is when homeostatic replication and virion based infection has ceased. It is satisfactory that this point is not way too close to meds initiation. and good to know that it exists! The system is converging.

BTW, I am convinced that in rare patients, the system is not converging; the 2 lines never cross.

More over, the uninfected cell pool is not taking an exponentially explosing shape, so that we are not ending with a million CD4/mL ;-)

confronted to actual lab test results:

Here again the picture is quite satisfactory: all data points are included within the 2 envelopes of our model: CD4 reading are never less than the modelized uninfected cells and never more than uninfected + infected (red line). Blue line cells have a 'normal' half life, whereas red line is a mix or 'normal' half live and 'shortened' half life (due to the infection)

revisit log and sine trending*********************For easier understanding, I have used Excel default Log trending.In fact, Log trending is satisfactory at first glance, but Log is an ever increasing function and after a few year you'd find yourself with thousands of 'healthy' CD4s per mLTherefore we have to change trending to one that is asymptotic.The following work great for both the blue and red envelopes

I kind of implied that CD4 fluctuations are a sine function. Look at the curvature: it is not! Of course, it may help understand this key point: CD4 count go up and down, but NOT erratically: there are driving forces to make it go up and driving forces to make is go downFor the sake of accuracy, let's just forget the sine model, since this is a succession of exponential and quadratic curves(Quiz for the chemical mind, just a hint: this is a mirror pattern to a Maxwell-Boltzman equation. Have fun!)

(*) changes:- replaced the SCQD data points by their all new exponential fit for clarity- changed color of upper envelope to orange so that red is free for infected- introduced months where VL became <50 and <20- Unchanged : point A and G

The Viramune Paradox unveiled earlier (higher initiation risk, very good long term results), certainly lies on meds ability to diffuse in all anatomic compartments.Makes life easier: no need to modelize anatomic compartments.

Why these models and why share here?- SCQD was originally designed to support a proof of concept for a new class of meds (thus, grants, funding and patenting...)- Share because my numbers & graphs have little interference from 'noise' such as CMV, HVC, thus easier to visualize- Graphic perspective may help those uncomfortable w/ V&K or meds- Finally... This is FUN !

Differing from empirical models, SCQD is a mechanistic model: we suggest a mechanism, write (differential) equations, solve, then find unknowns by best fit methods to get our initial data grid. (blue and red squares)

Changes- individual data points removed for clarity- dashed lines are either data, model or result lines- solid lines are their Log / Exp / Linear fits (see dress code)- introduced point E for ExtinctionSoon we will include CD8s and past point G data !

Of interestA- CD4 lab test (green dashed) results average (green solid) is like an arrow entering the funnel-like envelopes. This is why we needed this upper envelope, as it demonstrates the funnel nature of convergence (hence extinction)B- We easily see: CD4 lab test show an remarkably stable limit cycles, dampened in amplitude with the time to complete a cycle going longer and longer (remember, time axis is a log scale!)

Quiz: what set of differential equations give this type of limit cycle ?

Like all good Darwinians, we look toward theory to guide us through the plethora of factsrecommended readingsChomont's group produce real good stuff. Had to read several times to realize how groundbreaking this might be...Programmed Death-1 Is a Marker for Abnormal Distribution ...http://www.ncbi.nlm.nih.gov/pubmed/23918986

The following is very obscure, BUT, in someway, it resembles the mathematical model underlying those graphs I am showing here. Just scroll down past the equations (*) and go right to the graphs p. 23-26.Don't they look pretty much like those on my posts above ?

Aren't this immuno-dynamics (straight) lines amazing ? (remember in this dress code a straight line can hide either of LOG/Linear/EXP)

about Quiz and Twitter: the quiz hints will appear on the twitter line feed. So regular followers get a bonus primerTinyUrLs are to be created with direct pointer to key 'chapter' headers in this thread (for easier navigation and reference), then to individual 'main' post later on

Answers lots of questions: why 3 molecules? Why CD8 are so important in controlling the dynamics? Why is modelling so important, etc.

We will use data found in this one, not free, but the supplemental table isEffect of CMV-induced immune response, ... ANRS CO3 cohorthttp://tinyurl.com/oowe8rn

Why we need a good understanding of Pharmacodynamics? Well... If we want a PharmaCure, or understand the Viramune Paradox, or what to expect once achieved extinction/eradication, or how we prove it, how we reduce time-to-market, etc.

Yet, we need a pause in graphing as I am short of post-G data (takes 1 year to get 6 points... and I missed 2 labs, so ...)So why don't we play with this funny CD4/CD8 ratio in the interim?

CD4/CD8 ratio is of interest because it is the only surrogate marker for reservoir depletion that you and I can easily have access to. I had 2 labs with Proviral DNA (back in 2012) and still working on these research guys to give them to me...It is also a component to multiple T-cell marker recovery (MTMR), defined as CD4+ T cells >500/mm(3) plus %CD4 T cells >29% plus CD4+/CD8+ T-cell ratio >1.

Because it is a composite parameter, it is hard to master. But let's start with this: in the uninfected population its range is 1 to 4. Not a 'normal' Gaussian distribution, but a skewed, Log-normal distribution, like:http://tinyurl.com/k7re5wf

It is 'centered' on 1.7 (and not 2.5, as you might expect)This one below provides a slightly lower range, but, here again, the mean is not at the center, the distribution is slightly skewedhttp://tinyurl.com/qy54ngd

Do people who have normalized their ratio, have a normal ratio ?

Say, one Hiver under meds has a ratio of 1.2: ratio is back to 'normal'. But, if ALL Hivers, with 'normal' ratio, have a ratio of 1.2, then this population, as a group, is not 'normal'.

Quite fortunately, it appears to be normal. In the absence of table data (infected/normalized and uninfected), we can only compare distribution mode and skewness. If they are similar, then the distribution very likely are

Pr Siliciano's original set of equation (2003) is all about Target cells and Infected cells (within-patient infection). In population and adaptive dynamics, the targets are named Susceptibles, Infected: Infected (aka Zombies), and... Cured: Removed, Recovered or Imunized-Recovered.(aka SIR, Predator-Prey model and here SZR)

These are autonomous differential equations... Seemingly simple, they have no analytic solution, and can only be approximated numerically

When making some assumptions, it is possible to solve limit equations by calculus. This is a cornerstone to Siliciano's work and to the Latency Theory. Yet, some of the assumptions, dating 2003, may have to be revisited

somehow, I felt an urge to play with my ... random generator, testing robustness.The one that amused me most is to generate CD3% (CD3% be herefrom considered as CD3% = CD4% +CD8%), between its observed boundaries 65% to 75%

Then use the measured CD4% to calculate the CD4/CD8 ratio as CD4%/(CD3%-CD4%) and plot over the measured CD4/CD8 ratio.

At page 183: The virus seeks to derive the maximum benefits from the cell's replicative machinery at the least cost to itself

Not free, PDF exists:Handbook of regression and modeling (applications for the clinical and Pharmaceutical industries) by Daryl Paulson 2006Not my favorite, but has a lot of self learning tables, examples, figures and is ubiquitous in clinical labs. Lowdown: mostly linear regression

Those not understanding the basics of triphasic cell decay (hence VL decay), see fig 3.5 (scroll down on amazon's look inside). The graph gives a good approx. idea

Let's do derivation as per Delta(R)/Delta(T) = R(t) - R(t-1) / (t) - (t-1), as we have a fairly frequent sampling, and plot dR / dT as a function of R (R defined as CD4/CD8 ratio) and plot vs R (for ease of use I'll use, abusively, d in place of Delta). We can then do a convincing nonlinear, exponential, regression (not covered by Paulson)

So my doc, who made predictions only twice (at month 6 to predict that R will 'normalize' to 1, and when R was 1.9, saying it will go down) did this at very limited risk. He who sees many patients, has 'visually' integrated this basic rule that raises his credibility at minimal statistical cost, as lab tests tends to make him right. In this perspective, then, 1 is an attractor of R; R should converge to 1 and stay around there: this is statistically correct but dynamically wrong

Wrong ? What is wrong ? How do we know it is wrong ? 1 is (interestingly) a magic, pivotal, number for R (being at least the rounded lower value for 'normal' range), but is NOT a universal attractor

Just looking at the graph posted here: http://tinyurl.com/nw65oxqwe know that 1 is not an attractor for CD4/CD8 ratio: there are 3 subgroups clustered in 2 groups: those with ratio > 1, who cluster around 1.4 - 1.5 ; we did the maths here: http://tinyurl.com/jwcgptj

For those with ratio < 1, we use Chomont's data and find that they cluster at 0.68So, statistically there are (at least) 2 statistically stable attractors: 0.7 and 1.4. We will see later one that there may be a transient attractor at 1.0 and may be a stable attractor at 2.8, but we are not yet there

The problem with R (aka CD4/CD8 ratio) lies in its composite nature. If you own stocks labelled in a foreign currency, your portfolio may go up because the stock go up OR that foreign currency goes up and vice versa. And when CD4% goes up significantly, then CD8% is likely a go down at least a bit...This makes R more volatile than the underlying trend is.To correct for this we introduce a mathematically more rugged animal: Ropt, optimized ratio, the calculation of which goes beyond the spirit of this thread. The algorithm is not that complex, but, I assume the reader does not really bother. Any signal processing minded person knows the trick. So it is not so much what Ropt is that matters, but rather that it is a better toy to play with.

Let's plot R and Ropt. As you can see below they are not very different, similartrends, except that Ropt is, thus far, more stable

Next post:Exploring a new territory with Ropt derivation: Ropt goes to the Yukon !

While there is little on CD4 and CD8 dynamics, some recent articles are highlighting the driving forces underneath CD4 and CD8 population dynamics. To make it short, the underlying forces are independent in trend and linked in their maximum (aka carrying capacity): CD4 have an autonomous, self fueled proliferation pattern where CD4 growth is driven by ... CD4s themselves. And CD8 have a proliferation pattern driven by signs of infections (such as free RNA, aka VL and signaling infected cells)

Graph on my previous post is showing one thing of interest: we are now 3 and 1/2 years into a treatment started quite early and we see, on the ratio trend, that the immune restoration is still in progress. This graph is better than a thousand words to show the importance of time in recovery. The median treatment time in the SMART study was 3.5 y... Why would anyone be hopefull that treatment interruption can be successful if the recovery is still in progress ?

Earlier, we had graphed the derivative of R: a nice but not over exciting exercise. Today, I am posting a graph that I think is quite unique. Let's graph the derivative of R-opt (aka dRopt/dt, or speed, if you want) vs Ropt.

I had to move, very marginally, the X coordinates of 3 data points, to improve clarity. Even marginally edited for educational purposes, this graph is much more exciting. There you go:

Most natural systems evolve according to multistep processes. We refer to these dynamics as punctuated evolution

Nonequilibrium systems evolve in time, not according to a smooth or gradual fashion, but by going through periods of stagnation interrupted by fast changes.

I have finally found ways to graph the multistep changes in a very convincing manner, so next posts are going to be exiting!

I am not losing focus: show the 'unfortunate' users of 'low cost' NVP that its very simple structure makes it a very good ally in reservoir lowering strategies.

Yet, non-progress may involve steps forwards and steps backwards, and, I'd like to make sure that progress is sustained. 2013 started with mixed results with ratio flickering around 1. For 6 months now we have repeatedly had a ratio > 1.4

So we can look forward to 2014

In next posts, I'll explain the significance of the above graph, move to another very exiting graph, review my latest tricks against 'brain fog', anxiety and sleep issues and finally explore if our (earlier defined) point G is an extinction point of sorts and see when we can hope to reach a point where we can experiment further.

I remain convinced that remission is possible. It is just a matter of time until we find the keys to the challenging hurdle

This is Xmas time, so no maths for this post. Feel free to throw a marble (or glass sphere) in your cereal bowl, watch the movement, speed, etc. in case you have forgotten about potential wells. We may need that...

I did not like 2013 much. But I have enjoyed the 1400 CD4, and the PMs, and the graphs, and time spent with you guys.

A : no thanks; B : Somewhere, sometime, most likely the best, but, not in our reach; D : We can learn from them, but if the prerequisite is that you get meds within a few days of infection, then, as far as I am concerned, it's too lateC (Pharmacure) is slow progression from one status to another until We reach ultimate favorable factors and see if a remission is possible

Thus we need to define these 'status': the left hand side of our cursor is disease, the right side is 'cured' and there are things in between that are step stones towards the cure itself.

The T-cell homeostasis is unusual, interesting... This is not something we consider much. Yet, at baseline, 32% of patients had lost homeostasis. Not everyone recovers this. If you do not know your CD3%, just add CD4% + CD8% and you are about right. So, if you do not have access to CD3% , per se, substitute with (CD4% + CD8%)

Only 2% of patients meet the 3 criterias. Of note, achieving a normal CD4:CD8 ratio was not associated with better clinical outcome.

Interestingly, 99% exhibited ratio dysregulation at baseline... In other words, in that game, we all start in the same line, pretty much like in a video or role game.Patients initiating meds at CD4 600 have a head start in the CD4 contest, but, notin the ratio marathon. For me, CD4 T-cell count >532 cells took 3 weeks but CD4:CD8 ratio >1.2 took ... 3 years !

Pretty much as in cross country or cycling, how fast you get to the goal depends on the relief or terrain (aka topography). And recording speed tells you about the map ... Revealing the underlying terrain ... This is exactly what my latest graph aims at.

CD4/CD8 ratio is the only patient available signature for a lower reservoir. Until we have something better... We are exploring Pharmacure(s) and lower reservoir appears valuable if you are contemplating treatment simplifications or interruptions. For Viramune users, reducing one molecule does not seem to be a viable option ;-)

If you do not understand or remember the concept of potential well and what follows, do not worry, I have a newer graph ready to go which is much easier to understand. Need be, see : http://tinypic.com/r/x43n8x/5

Once you have the speed profile at first pass, the underlying potential is revealed: the higher speed is at the bottom of the (cereal) bowl and lower to zero speed at the vertical so we just need to flip the curve upside-down. The terrain reveals 3 zones and 2 to 3 attractors: 0.7 ; 1.4 and maybe 1

Well... We are done with this for the time being... We now have a map!

Our entertaining journey through the mathematics of Zombies showed that the set of equations derived from N compartment trafficking (Suceptibles, Infected, Removed ...) is sized (at least) N x N. So the minimum is 9 (which may be reduced to 6 through blunt simplifications), not withstanding additional parameters (degrees of freedom) such as time delays.

When I have time, I'll show a fairly successfull, Zombie-like numerical and graphic dynamics of the immune system.

In any case, the degrees of freedom are too many: we will not have enough data points to estimate them... We sense that there is a set of equations underlying our observations (lab test) but we can't resolve the complexity. There is a turn around:

The logistic equation, advanced by Verhulst, has been the workhorse model for describing the evolution of various social, biological, and economic systems. Resulting in a 4 parameters Logistic curve (aka S curve) for symmetric datasets and extended to 5 Parameters Logistic curve (5PL- S curve) for asymmetric datasets, it has proven at least as good as the complete Mass Action Equations (*) in modelling phenomena showing this common pattern:1- (slow) start (almost zero speed)2- increasing speed to a single maximum3- lowering speed4- (slow) end (saturation) (almost zero speed)See: http://en.wikipedia.org/wiki/Logistic_function

The S-curve demonstrate the efficacy of an intervention (here the introduction of HAART), such as a Receptor/ligand binding or inhibitors, which we are familiar with. If the intervention is efficient, then, we should find an S-curve that clearly reveals efficacy. BTW, that could be a more discriminant efficacy indicator than non-inferiority clinical trials which require too many patients and would allow to work with smaller cohorts, at a lower cost.

Every problem is obsessively simple when explained. If you can't explain it simply, you don't understand it well enough.

Thanks for messages and support. Indeed, if you want to keep a post short, it is condensed and too rich, difficult to digest. I'll try my best... Special thanks to X, St, HfC, ...

For the newer generation

recommended readings

Oddly enough, this very post. Yes... The graph below wasn't ready for CROI2014 submission deadline. LOL. Well I hope you will appreciate the value of this graph, which is 100% based on patient accessible data, is the result of higher frequency blood draws and creative graphing. The data acquitions spans over more than 3 years and have been timely reported here.

We've reached our destination (lower reservoirs): that is not disputable. The depletion may have been achieved around Jan 2013, but another set of 6 data points have been necessary to complete the curve below. We travelled under favourable winds.

The S curves have one advantage that make them a decisive tool in chemistry, biochemistry, pharmaceutical design and many other effective sciences. The likelyhood that data points will align along an S curve by pure chance is virtually zero. This has to do with the Confidence Intervals (CI) which I have reported on the graph (black fine lines are at CI 95%). In the sharper increase phase of the S the confidence intervals are very narrow, so the likelyhood that S showed up by chance is very very small.

Part A (first potential well) of our graph had lead us to an S-curve in that region, the later part of the same graph (say... C) leads to another S curve... The B area is flat, showing no trend...Are the S-curve nothing but a mere re-graph of our speed graph with 2 potential wells. Well... the graphs are not unrelated, but we are not redrawing the same thing in a different representation space. In Speed curve we have plotted dR/dT (the speed of R) vs R, here, we are plotting Ropt vs TIME. While R, Ropt, dR/dT are known with some uncertainty, TIME is defined accurately. There is a margin of error in the X AND Y axis of speed on potential well curves. On S curves, the uncertainty is only on the Y axis.

This second S curve unveils a second kick, that comes well after initiation. The graph is partial as I have isolated the second S-Curve. The delayed efficiency is, in amplitude, similar to the initial efficiency: the ratio is almost doubled each time (it just looks bigger, but it is not)

- we now have Viramune / generic Viramune and Viramune XR: which one to choose: I have recently received Generic Viramune, so I'll try it- Viramune detox- understanding NVP (and EFV) Pharmacokinetics : how you can benefit from knowing more about your meds- revised, detailed Viramune stop procedure based on recent analysis from SMART study trial and 'tail covering' trials

Reservoir reduction

- a combined graph with both S-curves on the same graph- database driven graphs (*) so that I can update graphs- exploring Post-G data and explaining treatment punctuations- CD4 > 1000 : is this a good thing ?- developping R-opt 2.0

Posting with graphs

Is fun, makes things easier to understand.GIF or JPEG graphs cannot be maintained as time goes.

(*) Currently looking for a SVG enabled, computation enabled service where I can port the graphs to.